St. Paul’s Cathedral in London has its own unique acoustics. The architecture of the dome allows a whisper to be heard from anywhere within the circular gallery, so-called the whispering gallery. The invention of whispering-gallery-mode (WGM) biosensors is indeed derived by this special gallery in St. Paul’s: just like a sound wave travelling within the dome, a light beam traveling within a glass sphere (in this case, a biosensor) circles multiple paths so that any molecule on the surface can be detected. Thanks to this powerful technique, interactions of unlabeled molecules can be analyzed with high sensitivity in real-time.
In early March of 2017, researchers from Max Planck Institute and University of Exeter published a comprehensive review paper in Lab on a Chip, explaining the advances of WGM sensors as scientific laboratory instruments, their development into lab on a chip devices, major challenges on the way towards real-world applications, and potential future applications.
WGM sensors probe the interaction between molecules and electromagnetic waves during a biomolecular reaction, and convert this information to a measurable signal. The probing is made possible thanks to the electromagnetic modes formed inside a resonator with axial symmetry. However, the electromagnetic waves slightly extend into the surrounding medium. Any changes in the surrounding medium, and therefore in the evanescent field, cause a shift of the resonance frequency—this is the basis of the sensing mechanism. WGMs are capable of sensing this shift in three ways: (1) Resonance frequency shift based sensing: measurable signal is the magnitude of the frequency shift, and the sensitivity of the sensor, which scale with the evanescent field strength at the distortion’s position, i.e. interaction of a single atomic ion with a plasmonic nanoparticle (Figure 1a). (2) Loss based sensing: it is based on the resonator’s energy loss per light wave oscillation, i.e. binding of polystyrene nanoparticles (Figure 1b). (3) Mode-splitting based sensing: a scattering molecule/particle couples clock-wise and counter clock-wise propagating WGMs, resulting in the formation of two different standing wave modes, i.e. deposition of multiple nanoparticles on a surface (Figure 1c).
The review also focuses on several performance criteria of WGM sensors, such as single molecule sensitivity, time resolution, stability and specificity. Single molecule sensitivity of WGM sensors depends on the resonator’s size, the surrounding medium and excitation wavelength. Despite the fact that these parameters seem to limit the sensitivity, increasing the electric field inside a nanoscale volume significantly can circumvent this problem. Apart from that, WGM sensors can detect events happening in milliseconds to seconds whereas these detection speeds are mostly limited by the equipment, for example, the laser’s maximum scanning speed. When it comes to stability of WGM sensors, one common problem is reported to be the environmental noise sources, affecting the reliability of the measurements. A variety of methods to reduce those negative effects are further discussed in the review. One another notable functionality is that WGM sensors can be as specific as probing a surface-immobilized receptor molecule reacting with an analyte of interest.
Lab on a chip applications of WGMs are discussed in two categories in the review (Figure 2): Planar resonators let the light to be coupled into multiple ring-resonators that are connected to channels containing different analytes. This type of resonators is low-cost and allows for in-parallel probing of samples. Pillar-supported high Q cavities is the second type, featuring a high Q factor owing to the air-gap between the substrate and the cavities. Pillar-supported resonators are high-cost due to several fabrication difficulties. Apart from those, droplet-based in vivo sensing via WGM sensors is also addressed as an alternative approach with the possibility of using the analyte medium itself as a resonator. Over the past decade, WGM sensors have been widely exploited to study molecular interactions with high sensitivity and seem to gain more and more attention.
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Eugene Kim, Martin D. Baaske and Frank Vollmer
Lab Chip, 2017, Critical Review
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About the Webwriter
Burcu Gumuscu is a postdoctoral fellow in BIOS Lab on a Chip Group at University of Twente in The Netherlands. Her research interests include development of microfluidic devices for quantitative analysis of proteins of a single-cell, next generation sequencing, compartmentalized organ-on-chip studies, and desalination of water on the microscale.